Project Summary Metastasis is the primary cause of morbidity and mortality in cancer with little improvement in outcomes over the past decade. This is particularly evident in gastrointestinal cancers where metastasis to the liver is the most common site of cancer cell spread. We hypothesize that the spread and growth of cancer cells in the liver is dependent on formation of a reversible niche environment that is directed by hepatocytes, the chief functional cells of the liver. In support of this hypothesis, we have found that primary tumors release soluble factors that activate hepatocytes in the liver. This process begins during the earliest stages of cancer development. Activated hepatocytes respond by releasing acute phase reactants which orchestrate a niche environment in the liver that is underpinned by the recruitment of neutrophils and myeloid cells and the deposition of extracellular matrix proteins. This environment supports cancer cell seeding and colonization. In the absence of this pro-metastatic niche, disseminated cancer cells enter a state of cell dormancy in the liver. Although macrophages are a first- line of defense against metastasis to the liver, their biology is also altered during formation of the niche environment in the liver. Thus, our findings identify an intercellular network within the liver underpinned by hepatocytes that responds to cancer development by preparing the ?soil? that supports cancer cell ?seeding?. Our ultimate goal is to devise novel therapies that will resolve the pro-metastatic niche and redirect the liver environment from pro- to anti-metastatic for treating and preventing cancer metastasis. However, this will require an understanding of the signals by which hepatocytes direct formation of the niche and identification of strategies capable of reversing the pro-metastatic potential of the niche. Therefore, in Aim 1, we will define the downstream signals by which hepatocytes coordinate formation of a pro-metastatic niche in the liver. In Aim 2, we will identify strategies to shift the niche environment in the liver from pro- to anti-metastatic. In Aim 3, we will investigate the impact of hepatocytes on cancer cell dormancy in the liver and the efficacy of cytotoxic chemotherapy. Together, these complementary aims will inform the development of therapies designed to condition the liver for anti- metastatic potential as a strategy to prevent and treat cancer metastasis.